The endothelial dysfunction is a predictor of occurrence for many diseases of cardiovascular system and a key link in their pathogenesis, formation and progression of clinical manifestations. Despite the large number of experimental and clinical researches, separate links of pathogenesis of heart endothelial cell damage under stress and in case of its combination with hypercholesterolemia require the further examination. The aim of the work was to investigate the role of nitric oxide, prostaglandins and antioxidants in the pathogenesis of endocardial endothelium damage (by the content of free fatty acids in it and the number of exfoliated cells) as a result of emotional and pain stress and stress complicated by hypercholesterolemia. An electro-impulse model was used to reproduce the stress. Alimentary hypercholesterolemia was modeled by keeping animals on an atherogenic diet for 2 months. To establish the role of individual pathogenetic links in the mechanisms of endotheliocyte damage, animals were administered the following pharmacological drugs: L-arginine (a substrate for the synthesis of nitric oxide), a prostaglandin synthesis blocker indomethacin, and prostenon (a synthetic analog of prostaglandin E2, which has an antioxidant effect). The state of endocardial endothelium was examined by using the light microscopy, analyzing the smears-imprints from macropreparations of ventricles by counting the number of endothelial cells in them. The content of free fatty acids was determined by the radiochemical method. It was shown that L-arginine significantly limits the damaging effect of the studied pathogenic factors on endocardial endothelium, reducing the number of exfoliated cells. The use of prostenon gives a slight, statistically unreliable positive effect. The use of indomethacin increases the damage of endothelial cells, which indicates the cytoprotective effect of prostaglandins under stress. All three studied preparations have no significant effect on the metabolism of free fatty acids both in case of “pure” emotional and pain stress and under stress complicated by hypercholesterolemia. The hypercholesterolemia of alimentary origin significantly limits the cytoprotective effect of L-arginine and prostenon on endocardial endothelium under stress action. In relation to indomethacin, in this situation, an increase of cell desquamation is observed, which indicates a decrease of prostaglandins protective effect.